Publications by authors named "Daniel Hammer"

228 Publications

Multivariable Dependence of Acoustic Contrast of Fluorocarbon and Xenon Microbubbles under Flow.

Ultrasound Med Biol 2021 Jun 7. Epub 2021 Jun 7.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Microbubbles (MBs) are 1 to 10 µm gas particles stabilized by an amphiphilic shell capable of responding to biomedical ultrasound with strong acoustic signals, allowing them to be commonly used in ultrasound imaging and therapy. The composition of both the shell and the core determines their stability and acoustic properties. While there has been extensive characterization of the dissolution, oscillation, cavitation, collapse and therefore, ultrasound contrast of MBs under static conditions, few reports have examined such behavior under hydrodynamic flow. In this study, we evaluate the interplay of ultrasound parameters (five different mechanical indices [MIs]), MB shell parameter (shell stiffness), type of gas (perfluorocarbon for diagnostic imaging and xenon as a therapeutic gas), and a flow parameter (flow rate) on the ultrasound signal of phospholipid-stabilized MBs flowing through a latex tube embedded in a tissue-mimicking phantom. We find that the contrast gradient (CG), a metric of the rate of decay of contrast along the length of the tube, and the contrast peak (CP), the location where the maximum contrast is reached, depend on the conditions of flow, imaging, and MB material. For instance, while the contrast near the flow inlet of the field of view is highest for a softer shell (dipalmitoylphosphatidylcholine [DPPC], C16) than for stiffer shells (distearoylphosphatidylcholine [DSPC], C18, and dibehenoylphosphatidylcholine [DBPC], C22), the contrast decay is also faster; stiffer shells provide more resistance and hence lead to slower MB dissolution/destruction. At higher flow rates, the CG is low for a fixed length of time because each MB is exposed to ultrasound for a shorter period. The CG becomes high for low flow rates, especially at high incident pressures (high MI), causing more MB destruction closer to the inlet of the field of view. Also, the CP shifts toward the inlet at low flow rates, high MIs, and low shell stiffness. We also report the first demonstration of sustained ultrasound flow imaging of a water-soluble, therapeutic gas MB (xenon). We find that an increased MB concentration is necessary for obtaining the same signal magnitude for xenon MBs. In summary, this study builds a framework depicting how multiple variables simultaneously affect the evolution of MB ultrasound contrast under flow. Depending on the MB composition, imaging conditions, transducer positioning, and image processing, building on such a framework could potentially allow for extraction of additional diagnostic information than is commonly analyzed for physiological flow.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.04.025DOI Listing
June 2021

Immediate Teeth in Fibulas: Expanded Clinical Applications and Surgical Technique.

J Oral Maxillofac Surg 2021 Apr 19. Epub 2021 Apr 19.

Vice Director, Maxillofacial Oncology and Reconstructive Surgery, John Peter Smith Health Network, Fort Worth, TX.

Purpose: The placement of immediate implants and teeth during jaw reconstruction using a fibula free flap has increased in recent years. Modifications of traditional fibula reconstructive techniques are needed to maximize success. This technique has not been described in patients requiring simultaneous soft tissue reconstruction. Our patient cohort includes cases with malignant pathology and those requiring skin paddles.  With digital workflows and point-of-care 3D printing, surgery is no longer delayed weeks for prosthesis fabrication. The purpose of this case series is to demonstrate a single institution's experience with expanded clinical applications and surgical techniques that enable predictable outcomes for immediate teeth in fibula flaps.

Materials And Methods: Ninety-five implants were placed in 22 patients undergoing fibula reconstruction of the jaw with immediate implants and an immediate dental prosthesis. Skin paddles were used in 10 patients while 12 patients had native mucosa. Six patients were treated for malignancies and underwent postoperative radiation. Implant success and complications were compared between implants with skin paddles and implants with native mucosa.

Results: Of 95 implants, 92 implants integrated for a 97% integration rate. All 13 radiated implants in 4 patients integrated. All 36 implants adjacent to skin paddles in 10 patients integrated. Seven implants were lost in a delayed fashion 9 to 15 months postoperatively resulting in a 93% overall implant success rate. Of the 22 patients, diagnoses were benign pathology for 11 patients, malignant pathology for 6 patients, gunshot wounds for 3 patients, and osteoradionecrosis for 2 patients.

Conclusion: Immediate placement of dental prostheses on immediate implants during fibula reconstruction of the jaws can be performed with a high rate of predictability. This technique can be expanded to select patients needing skin paddles. Modifications of traditional fibula reconstructive techniques are helpful to minimize soft tissue and prosthetic challenges.
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http://dx.doi.org/10.1016/j.joms.2021.04.005DOI Listing
April 2021

Dissecting the microvascular contributions to diffuse correlation spectroscopy measurements of cerebral hemodynamics using optical coherence tomography angiography.

Neurophotonics 2021 Apr 25;8(2):025006. Epub 2021 Apr 25.

New York Medical College, Department of Physiology, Valhalla, New York, United States.

Diffuse correlation spectroscopy (DCS) is an emerging noninvasive, diffuse optical modality that purportedly enables direct measurements of microvasculature blood flow. Functional optical coherence tomography angiography (OCT-A) can resolve blood flow in vessels as fine as capillaries and thus has the capability to validate key attributes of the DCS signal. To characterize activity in cortical vasculature within the spatial volume that is probed by DCS and to identify populations of blood vessels that are most representative of the DCS signals. We performed simultaneous measurements of somatosensory-evoked cerebral blood flow in mice using both DCS and OCT-A. We resolved sensory-evoked blood flow in the somatosensory cortex with both modalities. Vessels with diameters smaller than featured higher peak flow rates during the initial poststimulus positive increase in flow, whereas larger vessels exhibited considerably larger magnitude of the subsequent undershoot. The simultaneously recorded DCS waveforms correlated most highly with flow in the smallest vessels, yet featured a more prominent undershoot. Our direct, multiscale, multimodal cross-validation measurements of functional blood flow support the assertion that the DCS signal preferentially represents flow in microvasculature. The significantly greater undershoot in DCS, however, suggests a more spatially complex relationship to flow in cortical vasculature during functional activation.
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http://dx.doi.org/10.1117/1.NPh.8.2.025006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071783PMC
April 2021

Integrating adaptive optics-SLO and OCT for multimodal visualization of the human retinal pigment epithelial mosaic.

Biomed Opt Express 2021 Mar 17;12(3):1449-1466. Epub 2021 Feb 17.

National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

In vivo imaging of human retinal pigment epithelial (RPE) cells has been demonstrated through multiple adaptive optics (AO)-based modalities. However, whether consistent and complete information regarding the cellular structure of the RPE mosaic is obtained across these modalities remains uncertain due to limited comparisons performed in the same eye. Here, an imaging platform combining multimodal AO-scanning light ophthalmoscopy (AO-SLO) with AO-optical coherence tomography (AO-OCT) is developed to make a side-by-side comparison of the same RPE cells imaged across four modalities: AO-darkfield, AO-enhanced indocyanine green (AO-ICG), AO-infrared autofluorescence (AO-IRAF), and AO-OCT. Co-registered images were acquired in five subjects, including one patient with choroideremia. Multimodal imaging provided multiple perspectives of the RPE mosaic that were used to explore variations in RPE cell contrast in a subject-, location-, and even cell-dependent manner. Estimated cell-to-cell spacing and density were found to be consistent both across modalities and with normative data. Multimodal images from a patient with choroideremia illustrate the benefit of using multiple modalities to infer the cellular structure of the RPE mosaic in an affected eye, in which disruptions to the RPE mosaic may locally alter the signal strength, visibility of individual RPE cells, or even source of contrast in unpredictable ways.
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http://dx.doi.org/10.1364/BOE.413438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984802PMC
March 2021

Persistent Dark Cones in Oligocone Trichromacy Revealed by Multimodal Adaptive Optics Ophthalmoscopy.

Front Aging Neurosci 2021 9;13:629214. Epub 2021 Mar 9.

National Eye Institute, National Institutes of Health, Bethesda, MD, United States.

Dark cone photoreceptors, defined as those with diminished or absent reflectivity when observed with adaptive optics (AO) ophthalmoscopy, are increasingly reported in retinal disorders. However, their structural and functional impact remain unclear. Here, we report a 3-year longitudinal study on a patient with oligocone trichromacy (OT) who presented with persistent, widespread dark cones within and near the macula. Diminished electroretinogram (ERG) cone but normal ERG rod responses together with normal color vision confirmed the OT diagnosis. In addition, the patient had normal to near normal visual acuity and retinal sensitivity. Occasional dark gaps in the photoreceptor layer were observed on optical coherence tomography, in agreement with reflectance AO scanning light ophthalmoscopy, which revealed that over 50% of the cones in the fovea were dark, increasing to 74% at 10° eccentricity. In addition, the cone density was 78% lower than normal histologic value at the fovea, and 20-40% lower at eccentricities of 5-15°. Interestingly, color vision testing was near normal at locations where cones were predominantly dark. These findings illustrate how a retina with predominant dark cones that persist over at least 3 years can support near normal central retinal function. Furthermore, this study adds to the growing evidence that cones can continue to survive under non-ideal conditions.
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http://dx.doi.org/10.3389/fnagi.2021.629214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985087PMC
March 2021

Quantification of Retinal Ganglion Cell Morphology in Human Glaucomatous Eyes.

Invest Ophthalmol Vis Sci 2021 Mar;62(3):34

Center for Devices and Radiological Health (CDRH), U.S. Food and Drug Administration, Silver Spring, Maryland, United States.

Purpose: To characterize retinal ganglion cell morphological changes in patients with primary open-angle glaucoma associated with hemifield defect (HD) using adaptive optics-optical coherence tomography (AO-OCT).

Methods: Six patients with early to moderate primary open-angle glaucoma with an average age of 58 years associated with HD and six age-matched healthy controls with an average age of 61 years were included. All participants underwent in vivo retinal ganglion cell (RGC) imaging at six primary locations across the macula with AO-OCT. Ganglion cell layer (GCL) somas were manually counted, and morphological parameters of GCL soma density, size, and symmetry were calculated. RGC cellular characteristics were correlated with functional visual field measurements.

Results: GCL soma density was 12,799 ± 7747 cells/mm2, 9370 ± 5572 cells/mm2, and 2134 ± 1494 cells/mm2 at 3°, 6°, and 12°, respectively, in glaucoma patients compared with 25,058 ± 4649 cells/mm2, 15,551 ± 2301 cells/mm2, and 3891 ± 1105 cells/mm2 (P < 0.05 for all locations) at the corresponding retinal locations in healthy participants. Mean soma diameter was significantly larger in glaucoma patients (14.20 ± 2.30 µm) compared with the health controls (12.32 ± 1.94 µm, P < 0.05 for all locations); symmetry was 0.36 ± 0.32 and 0.86 ± 0.13 in glaucoma and control cohorts, respectively.

Conclusions: Glaucoma patients had lower GCL soma density and symmetry, greater soma size, and increased variation of GCL soma reflectance compared with age-matched control subjects. The morphological changes corresponded with HD, and the cellular level structural loss correlated with visual function loss in glaucoma. AO-based morphological parameters could be potential sensitive biomarkers for glaucoma.
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http://dx.doi.org/10.1167/iovs.62.3.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995922PMC
March 2021

A slow-growing anterior maxillary mass.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 Jan 29. Epub 2021 Jan 29.

Division of Maxillofacial Oncology and Reconstructive Surgery, John Peter Smith Hospital, Fort Worth, Texas.

A 43-year-old-male with no medical conditions presented to his dentist with a left maxillary swelling present for 1 year. His physical exam revealed a 2-cm × 2-cm, poorly demarcated, firm mass in the left anterior maxilla causing mobility of the associated teeth. He had a bluish discoloration of the anterior maxillary mucosa. A computed tomographic scan demonstrated a homogeneous and uniformly radiolucent, well-defined mass in the left anterior maxilla primarily involving the alveolus and the roots of teeth 7-12. The mass caused expansion and tooth displacement. An incisional biopsy was done and MUC 4 staining was diffusely positive so the diagnosis of low-grade fibromyxoid sarcoma (LGFMS) was made. He underwent wide local excision and reconstruction with a fibula free flap and a three-dimensionally printed, implant-retained prosthesis. The final pathology confirmed the diagnosis of LGFMS, stage pT4aN0M0, with negative margins. The patient had no evidence of recurrence at 1-year follow-up.
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http://dx.doi.org/10.1016/j.oooo.2021.01.021DOI Listing
January 2021

Considerations in Free Flap Reconstruction of the Midface.

Facial Plast Surg 2021 Feb 15. Epub 2021 Feb 15.

Otolaryngology and Facial Plastic Surgery Associates, Fort Worth, Texas.

Midface reconstruction has been a consistent challenge for reconstructive surgeons even with the significant advances in technology and technique achieved over the recent years. A meticulous preoperative assessment of the patient is required to properly assess the defect or anticipated defect, determine proper reconstructive surgical plan, and discuss expected functional and aesthetic outcomes with the patient. For years we have employed local flaps, regional flaps, obturators, alloplastic implants, free flaps, or a combination of the previously mentioned techniques to address complex midface reconstruction. Free flap reconstruction in the midface requires special considerations for the pedicle, flap selection, and flap design to ensure an optimal outcome. The introduction of virtual surgical planning for reconstruction has enhanced patient outcomes to include advances in immediate dental rehabilitation at the time of free flap surgery. Postoperative considerations including quality of life, functional and aesthetic outcomes, and management of complications will also be discussed.
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http://dx.doi.org/10.1055/s-0041-1722981DOI Listing
February 2021

Development, Validation, and Innovation in Ophthalmic Laser-Based Imaging: Report From a US Food and Drug Administration-Cosponsored Forum.

JAMA Ophthalmol 2021 01;139(1):113-118

Cornea Society, Fairfax, Virginia.

In April 2019, the US Food and Drug Administration, in conjunction with 11 professional ophthalmic, vision science, and optometric societies, convened a forum on laser-based imaging. The forum brought together the Food and Drug Administration, clinicians, researchers, industry members, and other stakeholders to stimulate innovation and ensure that patients in the US are the first in the world to have access to high-quality, safe, and effective medical devices. This conference focused on the technology, clinical applications, regulatory issues, and reimbursement issues surrounding innovative ocular imaging modalities. Furthermore, the emerging role of artificial intelligence in ophthalmic imaging was reviewed. This article summarizes the presentations, discussion, and future directions.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.4994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005310PMC
January 2021

Label-free adaptive optics imaging of human retinal macrophage distribution and dynamics.

Proc Natl Acad Sci U S A 2020 12 9;117(48):30661-30669. Epub 2020 Nov 9.

Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Radiological Devices, Food and Drug Administration, Silver Spring, MD 20993;

Microglia are resident central nervous system macrophages and the first responders to neural injury. Until recently, microglia have been studied only in animal models with exogenous or transgenic labeling. While these studies provided a wealth of information on the delicate balance between neuroprotection and neurotoxicity within which these cells operate, extrapolation to human immune function has remained an open question. Here we examine key characteristics of retinal macrophage cells in live human eyes, both healthy and diseased, with the unique capabilities of our adaptive optics-optical coherence tomography approach and owing to their propitious location above the inner limiting membrane (ILM), allowing direct visualization of cells. Our findings indicate that human ILM macrophage cells may be distributed distinctly, age differently, and have different dynamic characteristics than microglia in other animals. For example, we observed a macular pattern that was sparse centrally and peaked peripherally in healthy human eyes. Moreover, human ILM macrophage density decreased with age (∼2% of cells per year). Our results in glaucomatous eyes also indicate that ILM macrophage cells appear to play an early and regionally specific role of nerve fiber layer phagocytosis in areas of active disease. While we investigate ILM macrophage cells distinct from the larger sample of overall retinal microglia, the ability to visualize macrophage cells without fluorescent labeling in the live human eye represents an important advance for both ophthalmology and neuroscience, which may lead to novel disease biomarkers and new avenues of exploration in disease progression.
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http://dx.doi.org/10.1073/pnas.2010943117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720180PMC
December 2020

LFA-1 signals to promote actin polymerization and upstream migration in T cells.

J Cell Sci 2020 09 9;133(17). Epub 2020 Sep 9.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA

T cell entry into inflamed tissue requires firm adhesion, cell spreading, and migration along and through the endothelial wall. These events require the T cell integrins LFA-1 and VLA-4 and their endothelial ligands ICAM-1 and VCAM-1, respectively. T cells migrate against the direction of shear flow on ICAM-1 and with the direction of shear flow on VCAM-1, suggesting that these two ligands trigger distinct cellular responses. However, the contribution of specific signaling events downstream of LFA-1 and VLA-4 has not been explored. Using primary mouse T cells, we found that engagement of LFA-1, but not VLA-4, induces cell shape changes associated with rapid 2D migration. Moreover, LFA-1 ligation results in activation of the phosphoinositide 3-kinase (PI3K) and ERK pathways, and phosphorylation of multiple kinases and adaptor proteins, whereas VLA-4 ligation triggers only a subset of these signaling events. Importantly, T cells lacking Crk adaptor proteins, key LFA-1 signaling intermediates, or the ubiquitin ligase cCbl (also known as CBL), failed to migrate against the direction of shear flow on ICAM-1. These studies identify novel signaling differences downstream of LFA-1 and VLA-4 that drive T cell migratory behavior.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.248328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502589PMC
September 2020

On the axial location of Gunn's dots.

Am J Ophthalmol Case Rep 2020 Sep 1;19:100757. Epub 2020 Jun 1.

Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, 419 W. Redwood Street, Baltimore, MD, 21201, USA.

Purpose: To determine the axial location of Gunn's dots in the retina.

Methods: Adaptive optics scanning laser ophthalmoscopy (AOSLO) images and adaptive optics - optical coherence tomography (AO-OCT) volumes were collected from a region where Gunn's dots were found inferior to the optic disc from a subject determined by clinical examination to be a glaucoma suspect. AO-OCT volumes were also collected along the horizontal and vertical meridians from six healthy subjects and one glaucoma subject to identify and document other occurrences of Gunn's dots. AO-OCT volumes were registered in three-dimensions and averaged. Gunn's dots were segmented, and their volume, area, and diameter were measured.

Results: All Gunn's dots imaged in this study from all subjects were confined to the inner limiting membrane, neither extending into the vitreous nor into the nerve fiber layer. The size of the dots was highly variable. The measured volume, area, and diameter (mean ± standard deviation) were 1119.9 ± 590.9 μm, 220.2 ± 105.5 μm, and 14.3 ± 3.1 μm, the latter within the range as previously published reports.

Conclusions: Based upon evidence from this study and others, Gunn's dots are not thought to be Müller cell end-feet or hyalocytes. We hypothesize that they are related to microglia, either as the by-product of their phagocytosis function, or are actual dead ameboid-shaped microglia who have fulfilled their scavenger role in retinal pathology. Further studies are needed in diseased eyes to determine if they have predictive value.
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http://dx.doi.org/10.1016/j.ajoc.2020.100757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287238PMC
September 2020

Immediate Teeth in Fibulas: Planning and Digital Workflow With Point-of-Care 3D Printing.

J Oral Maxillofac Surg 2020 Aug 14;78(8):1320-1327. Epub 2020 Apr 14.

Assistant Fellowship Director, Division of Maxillofacial Oncology and Reconstructive Surgery, John Peter Smith Health Network, Fort Worth, TX.

Purpose: Point-of-care 3-dimensional (3D) printing has become more common in recent years because many hospitals have created 3D printing laboratories. Traditional techniques to fabricate an immediate dental prosthesis for fibula and implant reconstructions have involved outsourcing to dental laboratories. This results in delays, making it suitable only for benign disease. In the present report, we have demonstrated a technique for in-house creation of a 3D printed dental prosthesis for placement of implants at free fibula maxillofacial reconstruction. Our digital method has reduced costs and shortened the interval to surgery compared with traditional laboratory techniques.

Materials And Methods: Twelve patients underwent free fibula reconstruction of the mandible or maxilla with immediate implants and immediate teeth. A dental implant-retained restoration was created before surgery for immediate placement at fibula reconstruction. For the first 5 patients, the prosthesis was fabricated by a dental laboratory after virtual surgical planning. For the next 7 patients, the prosthesis was designed by the surgeon and 3D printed via the in-house laboratory. Four of these in-house cases were performed for malignant disease with skin paddles.

Results: All 12 patients received an immediate implant-retained fixed prosthesis at fibula reconstruction. The time required to generate the in-house 3D printed prostheses was significantly shorter than that required to create the dental laboratory-fabricated prostheses. The costs were also less with the 3D printed prostheses compared with the dental laboratory-fabricated prostheses.

Conclusions: The digital workflow we have presented eliminates the delay in creating a dental laboratory-fabricated provisional dental prosthesis for fibula and implant reconstruction. This allows for immediate dental restoration for patients with malignant disease previously considered unsuitable owing to the inherent delay required using an offsite dental laboratory. A decrease in cost to create in-house 3D printed prostheses was noted compared with the prostheses fabricated by a dental laboratory. Case selection is critical to predict the soft tissue needs for composite defects.
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http://dx.doi.org/10.1016/j.joms.2020.04.006DOI Listing
August 2020

Identifying sequence perturbations to an intrinsically disordered protein that determine its phase-separation behavior.

Proc Natl Acad Sci U S A 2020 05 11;117(21):11421-11431. Epub 2020 May 11.

Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015;

Phase separation of intrinsically disordered proteins (IDPs) commonly underlies the formation of membraneless organelles, which compartmentalize molecules intracellularly in the absence of a lipid membrane. Identifying the protein sequence features responsible for IDP phase separation is critical for understanding physiological roles and pathological consequences of biomolecular condensation, as well as for harnessing phase separation for applications in bioinspired materials design. To expand our knowledge of sequence determinants of IDP phase separation, we characterized variants of the intrinsically disordered RGG domain from LAF-1, a model protein involved in phase separation and a key component of P granules. Based on a predictive coarse-grained IDP model, we identified a region of the RGG domain that has high contact probability and is highly conserved between species; deletion of this region significantly disrupts phase separation in vitro and in vivo. We determined the effects of charge patterning on phase behavior through sequence shuffling. We designed sequences with significantly increased phase separation propensity by shuffling the wild-type sequence, which contains well-mixed charged residues, to increase charge segregation. This result indicates the natural sequence is under negative selection to moderate this mode of interaction. We measured the contributions of tyrosine and arginine residues to phase separation experimentally through mutagenesis studies and computationally through direct interrogation of different modes of interaction using all-atom simulations. Finally, we show that despite these sequence perturbations, the RGG-derived condensates remain liquid-like. Together, these studies advance our fundamental understanding of key biophysical principles and sequence features important to phase separation.
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http://dx.doi.org/10.1073/pnas.2000223117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261017PMC
May 2020

Experience With "Jaw in a Day" Technique.

J Craniofac Surg 2020 Jul-Aug;31(5):1212-1217

Otolaryngology and Facial Plastic Surgery Associates, Fort Worth, TX.

The "Jaw in a Day" (JIAD) technique, first described by Levine and colleagues, establishes immediate functional occlusion through a single-stage maxillomandibular reconstruction with concurrent implant placement and provisional prosthesis delivery. In this study, the authors describe 2 cases exemplifying the reconstructive principles of JIAD. One patient underwent mandibular reconstruction with the JIAD technique and another patient underwent JIAD with an optimized rapid sequence computer-aided design and computer-aided manufacturing (CAD-CAM) for composite maxillomandibular reconstruction. Immediate implant-borne prosthesis was fixated and all implants osseointegrated into the neomandible. Although the authors' patient outcomes are consistent with the literature, the published reports of JIAD remain limited, and further studies are required to assess the long-term functional and aesthetic outcomes as well as cost-effectiveness of this approach.
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http://dx.doi.org/10.1097/SCS.0000000000006369DOI Listing
January 2021

Ultrasound Responsive Noble Gas Microbubbles for Applications in Image-Guided Gas Delivery.

Adv Healthc Mater 2020 05 24;9(9):e1901721. Epub 2020 Mar 24.

Department of Radiology University of Pennsylvania Medical Center, Philadelphia, PA, 19104, USA.

Noble gases, especially xenon (Xe), have been shown to have antiapoptotic effects in treating hypoxia ischemia related injuries. Currently, in vivo gas delivery is systemic and performed through inhalation, leading to reduced efficacy at the injury site. This report provides a first demonstration of the encapsulation of pure Xe, Ar, or He in phospholipid-coated sub-10 µm microbubbles, without the necessity of stabilizing perfluorocarbon additives. Optimization of shell compositions and preparation techniques show that distearoylphosphatidylcholine (DSPC) with DSPE-PEG5000 can produce stable microbubbles upon shaking, while dibehenoylphosphatidylcholine (DBPC) blended with either DSPE-PEG2000 or DSPE-PEG5000 produces a high yield of microbubbles via a sonication/centrifugation method. Xe and Ar concentrations released into the microbubble suspension headspace are measured using GC-MS, while Xe released directly in solution is detected by the fluorescence quenching of a Xe-sensitive cryptophane molecule. Bubble production is found to be amenable to scale-up while maintaining their size distribution and stability. Excellent ultrasound contrast is observed in a phantom for several minutes under physiological conditions, while an intravenous administration of a bolus of pure Xe microbubbles provides significant contrast in a mouse in pre- and post-lung settings (heart and kidney, respectively), paving the way for image-guided, localized gas delivery for theranostic applications.
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http://dx.doi.org/10.1002/adhm.201901721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457952PMC
May 2020

Spindle Cell Sarcoma of the Maxilla: A Rare Entity, Case Report, and Review of the Literature.

J Oral Maxillofac Surg 2020 Aug 12;78(8):1334-1342. Epub 2020 Feb 12.

Fellow, Division of Maxillofacial Oncology and Reconstructive Surgery, John Peter Smith Hospital, Fort Worth, TX.

Spindle cell sarcoma (SCS) is a malignancy, with the most recent Surveillance, Epidemiology, and End Results (SEER) data citing a total of 250 reported cases occurring in the head and neck. Of these cases, none originated in the maxillofacial hard tissue. To the best of our knowledge, only 2 cases of primary osseous SCS of the maxillofacial region have been reported. These cases were not accounted for in the SEER data. The diagnosis of SCS requires its differentiation from other sarcomas and spindle cell neoplasms. Therefore, a comprehensive review to reinforce its inclusion in oral and maxillofacial surgeons' differential diagnosis for osseous neoplastic pathology is desired. In the present case report, we have described a maxillary SCS in a patient with an initial diagnosis of a spindle cell lesion of uncertain biologic behavior. We reviewed the data for SCS, including the epidemiologic data, diagnostic challenges, clinical and radiographic presentations, prognostic indicators, and treatment.
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http://dx.doi.org/10.1016/j.joms.2020.02.003DOI Listing
August 2020

SPLIT: Stable Protein Coacervation Using a Light Induced Transition.

ACS Synth Biol 2020 03 28;9(3):500-507. Epub 2020 Feb 28.

Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

Protein coacervates serve as hubs to concentrate and sequester proteins and nucleotides and thus function as membraneless organelles to manipulate cell physiology. We have engineered a coacervating protein to create tunable, synthetic membraneless organelles that assemble in response to a single pulse of light. Coacervation is driven by the intrinsically disordered RGG domain from the protein LAF-1, and opto-responsiveness is coded by the protein PhoCl, which cleaves in response to 405 nm light. We developed a fusion protein containing a solubilizing maltose-binding protein domain, PhoCl, and two copies of the RGG domain. Several seconds of illumination at 405 nm is sufficient to cleave PhoCl, removing the solubilization domain and enabling RGG-driven coacervation within minutes in cellular-sized water-in-oil emulsions. An optimized version of this system displayed light-induced coacervation in . The methods described here provide novel strategies for inducing protein phase separation using light.
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http://dx.doi.org/10.1021/acssynbio.9b00503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383129PMC
March 2020

Longitudinal neural and vascular structural dynamics produced by chronic microelectrode implantation.

Biomaterials 2020 04 31;238:119831. Epub 2020 Jan 31.

Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Radiological Devices, Food and Drug Administration, Silver Spring, MD, USA.

Implanted microelectrode arrays sense local neuronal activity, signals which are used as control commands for brain computer interface (BCI) technology. Patients with tetraplegia have used BCI technology to achieve an extraordinary degree of interaction with their local environment. However, current microelectrode arrays for BCIs lose the ability to record high-quality neural signals in the months-to-years following implantation. Very little is known regarding the dynamic response of neurons and vasculature in the months following electrode array implantation, but loss of structural integrity near the electrode may contribute to the degradation of recording signals. Here, we use in-vivo dual-modality imaging to characterize neuronal and vasculature structures in the same animal for 3 months following electrode insertion. We find ongoing neuronal atrophy, but relative vascular stability, in close proximity to the electrode, along with evidence suggesting links between rare, abrupt hypoxic events and neuronal process atrophy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119831DOI Listing
April 2020

Longitudinal multimodal assessment of neurodegeneration and vascular remodeling correlated with signal degradation in chronic cortical silicon microelectrodes.

Neurophotonics 2020 Jan 30;7(1):015004. Epub 2020 Jan 30.

Food and Drug Administration, Center for Radiological Devices, Office of Science and Engineering Laboratories, Division of Biomedical Physics, Silver Spring, Maryland, United States.

: Cortically implanted microelectrode arrays provide a direct interface with neuronal populations and are used to restore movement capabilities and provide sensory feedback to patients with paralysis or amputation. Penetrating electrodes experience high rates of signal degradation within the first year that limit effectiveness and lead to eventual device failure. : To assess vascular and neuronal changes over time in mice with implanted electrodes and examine the contribution of the brain tissue response to electrode performance. : We used a multimodal approach combining electrophysiology and subcellular-level optical imaging. : At acute timescales, we observed structural damage from the mechanical trauma of electrode insertion, evidenced by severed dendrites in the electrode path and local hypofluorescence. Superficial vessel growth and remodeling occurred within the first few weeks in both electrode-implanted and window-only animals, but the deeper capillary growth evident in window-only animals was suppressed in electrode-implanted animals. After longer implantation periods, there was evidence of degeneration of transected dendrites superficial to the electrode path and localized neuronal cell body loss, along with deep vascular velocity changes near the electrode. Total spike rate (SR) across all animals reached a peak between 3 and 9 months postimplantation, then decreased. The local field potential signal remained relatively constant for up to 6 months, particularly in the high-gamma band, indicating long-term electrode viability and neuronal functioning at further distances from the electrode, but it showed a reduction in some animals at later time points. Most importantly, we found that progressive high-gamma and SR reductions both correlate positively with localized cell loss and decreasing capillary density within of the electrode. : This multifaceted approach provided a more comprehensive picture of the ongoing biological response at the brain-electrode interface than can be achieved with postmortem histology alone and established a real-time relationship between electrophysiology and tissue damage.
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http://dx.doi.org/10.1117/1.NPh.7.1.015004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991888PMC
January 2020

Paramedian Forehead Flap.

Atlas Oral Maxillofac Surg Clin North Am 2020 Mar 25;28(1):23-28. Epub 2019 Dec 25.

Division of Maxillofacial Oncology and Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, John Peter Smith Hospital, 1500 South Main Street, Fort Worth, TX 76104, USA.

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http://dx.doi.org/10.1016/j.cxom.2019.11.003DOI Listing
March 2020

Integrin crosstalk allows CD4+ T lymphocytes to continue migrating in the upstream direction after flow.

Integr Biol (Camb) 2019 12;11(10):384-393

Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA.

In order to perform critical immune functions at sites of inflammation, circulatory T lymphocytes must be able to arrest, adhere, migrate and transmigrate on the endothelial surface. This progression of steps is coordinated by cellular adhesion molecules (CAMs), chemokines, and selectins presented on the endothelium. Two important interactions are between Lymphocyte Function-associated Antigen-1 (LFA-1) and Intracellular Adhesion Molecule-1 (ICAM-1) and also between Very Late Antigen-4 (VLA-4) and Vascular Cell Adhesion Molecule-1 (VCAM-1). Recent studies have shown that T lymphocytes and other cell types can migrate upstream (against the direction) of flow through the binding of LFA-1 to ICAM-1. Since upstream migration of T cells depends on a specific adhesive pathway, we hypothesized that mechanotransduction is critical to migration, and that signals might allow T-cells to remember their direction of migration after the flow is terminated. Cells on ICAM-1 surfaces migrate against the shear flow, but the upstream migration reverts to random migration after the flow is stopped. Cells on VCAM-1 migrate with the direction of flow. However, on surfaces that combine ICAM-1 and VCAM-1, cells crawl upstream at a shear rate of 800 s-1 and continue migrating in the upstream direction for at least 30 minutes after the flow is terminated-we call this 'migrational memory'. Post-flow upstream migration on VCAM-1/ICAM-1 surfaces is reversed upon the inhibition of PI3K, but conserved with cdc42 and Arp2/3 inhibitors. Using an antibody against VLA-4, we can block migrational memory on VCAM-1/ICAM-1 surfaces. Using a soluble ligand for VLA-4 (sVCAM-1), we can promote migrational memory on ICAM-1 surfaces. These results indicate that, while upstream migration under flow requires LFA-1 binding to immobilized ICAM-1, signaling from VLA-4 and PI3K activity is required for the migrational memory of CD4+ T cells. These results indicate that crosstalk between integrins potentiates the signal of upstream migration.
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http://dx.doi.org/10.1093/intbio/zyz034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946828PMC
December 2019

Identifying Key Pathways and Components in Chemokine-Triggered T Lymphocyte Arrest Dynamics Using a Multi-Parametric Global Sensitivity Analysis.

Cell Mol Bioeng 2019 Jun 29;12(3):193-202. Epub 2019 May 29.

Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd St., Philadelphia, PA 19104 USA.

Introduction: The arrest of rolling T lymphocytes at specific locations is crucial to proper immune response function. We previously developed a model of chemokine-driven integrin activation, termed integrative signaling adhesive dynamics (ISAD). In addition, we have shown that loss of diacylglycerol kinase (DGK) leads to a gain of function regarding adhesion under shear flow. We undertook this study to understand the sensitivity of adhesion to perturbations in other signaling molecules.

Methods: We adapted multi-parametric sensitivity analysis (MPSA) for use in our ISAD model to identify important parameters, including initial protein concentrations and kinetic rate constants, for T lymphocyte arrest. We also compared MPSA results to those obtained from a single parametric sensitivity analysis.

Results: In addition to the previously shown importance of DGK in lymphocyte arrest, PIP cleavage and Rap1 activation are crucial in determining T cell arrest dynamics, which agree with previous experimental findings. The l-selectin density on the T lymphocyte surface also plays a large role in determining the distance rolled before arrest. Both the MPSA and single-parametric method returned similar results regarding the most sensitive kinetic rate constants.

Conclusion: We show here that the regulation of the amount of second messengers are, in general, more critical for determining T lymphocyte arrest over the initial signaling proteins, highlighting the importance of amplification of signaling in cell adhesion responses. Overall, this work provides a mechanistic insight of the contribution of key pathways and components, thus may help to identify potential therapeutic targets for drug development against immune disorders.
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http://dx.doi.org/10.1007/s12195-019-00575-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816696PMC
June 2019

A simulation of the random and directed motion of dendritic cells in chemokine fields.

PLoS Comput Biol 2019 10 7;15(10):e1007295. Epub 2019 Oct 7.

Department of Chemical and Biological Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the "line of equistimulation;" this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study.
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http://dx.doi.org/10.1371/journal.pcbi.1007295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797211PMC
October 2019

Human Neutrophils Will Crawl Upstream on ICAM-1 If Mac-1 Is Blocked.

Biophys J 2019 10 18;117(8):1393-1404. Epub 2019 Sep 18.

Departments of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania; Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

The recruitment of neutrophils to sites of inflammatory insult is a hallmark of the innate immune response. Neutrophil recruitment is regulated by a multistep process that includes cell rolling, activation, adhesion, and transmigration through the endothelium commonly referred to as the leukocyte adhesion cascade. After selectin-mediated braking, neutrophils migrate along the activated vascular endothelium on which ligands, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are expressed. Previous studies have shown that two cells that commonly home from blood vessel to tissue-T cells and hematopoietic stem and progenitor cells-use the integrin lymphocyte functional antigen-1 (LFA-1) to migrate against the direction of shear flow once adherent on ICAM-1 surfaces. Like T cells and hematopoietic stem and progenitor cells, neutrophils express LFA-1, but they also express macrophage-1 antigen (Mac-1), which binds to ICAM-1. Previous reports have shown that neutrophils will not migrate against the direction of flow on ICAM-1, but we hypothesized this was due to the influence of Mac-1. Here, we report that both the HL-60 neutrophil-like cell line and primary human neutrophils can migrate against the direction of fluid flow on ICAM-1 surfaces via LFA-1 if Mac-1 is blocked; otherwise, they migrate downstream. We demonstrate this both on ICAM-1 surfaces and on activated endothelium. In sum, both LFA-1 and Mac-1 binding ICAM-1 play a critical role in determining the direction of neutrophil migration along the endothelium, and their interaction may play an important role in controlling neutrophil trafficking during inflammation.
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http://dx.doi.org/10.1016/j.bpj.2019.08.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817642PMC
October 2019

measurement of organelle motility in human retinal pigment epithelial cells.

Biomed Opt Express 2019 Aug 19;10(8):4142-4158. Epub 2019 Jul 19.

School of Optometry, Indiana University, 800 East Atwater Avenue, Bloomington, IN 47405, USA.

Retinal pigment epithelial (RPE) cells are well known to play a central role in the progression of numerous retinal diseases. Changes in the structure and function of these cells thus may serve as sensitive biomarkers of disease onset. While studies have focused on structural changes, functional ones may better capture cell health owing to their more direct connection to cell physiology. In this study, we developed a method based on adaptive optics optical coherence tomography (AO-OCT) and speckle field dynamics for characterizing organelle motility in individual RPE cells. We quantified the dynamics in terms of an exponential decay time constant, the time required for the speckle field to decorrelate. Using seven normal subjects, we found the RPE speckle field to decorrelate in about 5 s. This result has two fundamental implications for future clinical use. First, it establishes a path for generating a normative baseline to which motility of diseased RPE cells can be compared. Second, it predicts an AO-OCT image acquisition time that is 36 times faster than used in our earlier report for individuating RPE cells, thus a major improvement in clinical efficacy.
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http://dx.doi.org/10.1364/BOE.10.004142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701538PMC
August 2019

Management of Orbital Fractures.

Atlas Oral Maxillofac Surg Clin North Am 2019 Sep 25;27(2):157-165. Epub 2019 Jun 25.

Department of Surgery, Division of Oral and Maxillofacial Surgery, UT Southwestern/Parkland Memorial Hospital, 5323 Harry Hines Boulevard MC 9109, Dallas, TX 75390-9109, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cxom.2019.05.007DOI Listing
September 2019

Adhesive dynamics simulations quantitatively predict effects of kindlin-3 deficiency on T-cell homing.

Integr Biol (Camb) 2019 06;11(6):293-300

Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA.

Leukocyte adhesion is important for the proper functioning of the immune system. While leukocyte homing is mediated by adhesion receptors, the activation of these receptors is modulated by intracellular signaling molecules. In Leukocyte Adhesion Deficiency Type 3, the loss of the kindlin-3 prevents the activation of Leukocyte Function-associated Antigen-1 (LFA-1), which leads to a defect in adhesion, causing recurrent infections and bleeding disorders. Here, we use Integrated Signaling Adhesive Dynamics, a computer model of leukocyte rolling and adhesion combined with a simulated intracellular signaling cascade, to predict the response of T cells to depletion of kindlin-3. Our model predicts that cell adhesion is hypersensitive to the amount of kindlin-3 in the cell, while the rolling velocity is independent of kindlin-3 concentration. In addition, our simulation predicted that the time to stop, an important metric of adhesion, would increase with decreasing kindlin-3 expression. These predictions were confirmed experimentally in experiments using Jurkat cells with reduced expression of kindlin-3. These results suggest that Adhesive Dynamics is a versatile tool for quantifying adhesion in the immune response and predicting the effects of engineering cellular components.
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http://dx.doi.org/10.1093/intbio/zyz024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309535PMC
June 2019

Application of optical coherence tomography and optical path length method for monitoring corneal thickness and refractive index change during corneal cross-linking.

Appl Opt 2019 Jun;58(17):4616-4621

Corneal cross-linking (CXL) using UVA irradiation with a riboflavin photosensitizer has emerged as a new treatment paradigm for corneal ectatic disorders. The thickness threshold for protection of intraocular structures has often been challenged with ongoing developments, and corneal thinning becomes an important safety concern, especially for patients with thin corneas. In this study with an ex vivo bovine eye model, we monitored corneal thinning and corneal refractive index changes using optical coherence tomography (OCT) integrated with an adaptation of the optical path length method. CXL experiments were performed based on the standard protocol that includes removal of the corneal epithelium to facilitate diffusion of riboflavin into the stroma. The corneal stromal thickness and group refractive index were measured by a 1310 nm Fourier-domain OCT imaging system at three critical points of the procedure: immediately after epithelial removal, after 30 min riboflavin instillation, and after 30 min UVA irradiation with continuing instillation. We found that the refractive index of the bovine cornea changed significantly from epithelial removal to riboflavin instillation and UVA irradiation, increasing from 1.377±0.005 (mean±standard deviation) after de-epithelization to 1.387±0.003 after 30 min instillation and 1.388±0.008 after subsequent irradiation. The corneas also underwent a considerable decrease (10%-20%) in stromal thickness with thinning of 95±29  μm (mean±standard deviation) after riboflavin instillation and a further decrease (∼5%) with thinning of 42±19  μm after UVA irradiation. Our study highlights the importance of corneal thickness monitoring during CXL, especially after riboflavin instillation when the decrease is the largest, to avoid delivering endothelial cytotoxic doses. An increase in refractive index heightens the concern for corneal thinning and the need for careful monitoring as a safety precaution.
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http://dx.doi.org/10.1364/AO.58.004616DOI Listing
June 2019

3-D printed photoreceptor phantoms for evaluating lateral resolution of adaptive optics imaging systems.

Opt Lett 2019 Apr;44(7):1825-1828

With adaptive optics (AO), optical coherence tomography and scanning laser ophthalmoscopy imaging systems can resolve individual photoreceptor cells in living eyes, due to enhanced lateral spatial resolution. However, no standard test method exists for experimentally quantifying this parameter in ophthalmic AO imagers. Here, we present three-dimensional (3-D) printed phantoms, which enable the measurement of lateral resolution in an anatomically relevant manner. We used two-photon polymerization to fabricate two phantoms, which mimic the mosaic of cone photoreceptor outer segments at multiple retinal eccentricities. With these phantoms, we demonstrated that the resolution of two multimodal AO systems is similar to theoretical predictions, with some intriguing speckle effects.
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http://dx.doi.org/10.1364/OL.44.001825DOI Listing
April 2019